A Genetic and PET Imaging Study of a Schizophrenia Endophenotype

描述（由申请人提供）：精神分裂症具有显著的遗传风险。然而，导致疾病表型的特定基因尚未被确定。我们的替代方法是通过使用定义明确的神经生理/认知特征来简化问题，这些特征增加了遗传成分，有望标记疾病风险的子成分，从而在基因变异和翻译的蛋白质/功能之间找到特定的分子途径8。平滑追踪眼动（spm）异常是精神分裂症的生物学标志。在60多项精神分裂症的研究中，SPEM缺陷一直被重复出现，几乎没有负面结果。关注SPEM可能为精神分裂症的发病生理学提供新的见解。挑战在于将这种表型分解为其基本分子成分，以确定从基因到信号传导途径到行为和精神分裂症的途径。研究表明，预测追求收益（SPEM的一个组成部分）的缺陷可能是精神分裂症患者及其一级亲属的眼动追踪障碍的基础。预测追求增益测量比传统的SPEM测量在定义高危个体方面更敏感10-12。神经影像学研究已经确定了几个与精神分裂症患者SPEM缺陷相关的皮质区域。最一致的发现是，在SPEM13-15期间，额眼区（FEF）的激活减少。虽然FEF是控制SPEM的主要皮层区域，但最近的研究表明FEF对SPEM的控制是通过几个下行通路实现的。这种追求系统的功能性神经回路由皮质-纹状体-苍白球-丘脑-皮质回路组成，分布于中脑、颞叶、顶叶和前额叶皮层16-18。来自猴子和人类的新证据已经建立了从FEF到尾状核和黑质的密集传出投射，这些中继站在控制预测性追求的神经运动和认知过程中至关重要19-21。因此，FEF和尾状核是提出的试点研究中感兴趣的区域。多巴胺信号的失调，特别是在前额叶皮层，被认为是精神分裂症中几种神经认知缺陷的核心。预测追踪回路的重叠部分由多巴胺能神经传递调节，包括FEF和尾状核23；24。本研究将研究眼动追踪与精神分裂症患者和健康对照者FEF和尾状核中多巴胺转运体（DAT）密度之间的关系。第二个重点将是多巴胺转运体基因（DAT1）中功能可变串联重复数（VNTR）多态性和FEF和尾状核中DAT密度的影响。DAT密度是通过正电子发射断层扫描（PET）期间DAT特异性放射配体[11C]WIN 35,428的结合势来测量的。该研究的方法整合了离体分子生物化学，功能基因组学和体内神经成像方法。

DESCRIPTION (provided by applicant): Schizophrenia has a significant genetic risk. However, the specific genes that contribute to the disease phenotype have not been identified. Our alternative approach is to simplify the problem by using well-defined neurophysiological/cognitive traits that have increased genetic component and are expected to mark sub- components of disease risk and hence, specific molecular pathways between gene variants and translated protein/function8. Smooth pursuit eye movement (SPEM, also called eye tracking) abnormality is an established biological marker for schizophrenia. SPEM deficits have been consistently reproduced in over 60 studies of schizophrenia, with few negative results9. Focusing on SPEM can potentially provide new insights into the etiopathophysiology of schizophrenia. The challenge is to decompose this phenotype into its elemental molecular components in order to determine the paths leading from genes to signaling pathways to behaviors, and to schizophrenia. Studies suggest that deficits in predictive pursuit gain (a subcomponent of SPEM) may underlie the eye tracking impairment in schizophrenia patients and their first-degree relatives. The predictive pursuit gain measure is more sensitive in defining at-risk individuals than traditional SPEM measures10-12. Neuroimaging studies have identified several cortical regions associated with SPEM deficits in schizophrenia. The most consistently replicated finding has been, reduced activation in the frontal eye fields (FEF) during SPEM13-15. Although the FEF is the primary cortical area for the control of SPEM, recent studies have shown that FEF control of SPEM is effected through several descending pathways. This functional neural circuitry of the pursuit system consists of a cortico-striato-pallido-thalamo-cortical loop distributed through the midbrain, temporal, parietal, and prefrontal cortices16-18. Emerging evidence from monkeys and humans has established dense efferent projections from the FEF to the caudate nucleus and substantia nigra, and that these relay stations are critical in the neuromotor and cognitive processes that control predictive pursuit19-21. Thus, the FEF and the caudate are regions of interest in the proposed pilot study. Dysregulation of dopamine signaling, particularly in the prefrontal cortex, is considered to be at the core of several neurocognitive deficits in schizophrenia22. Overlapping components of the predictive pursuit circuitry are modulated by dopaminergic neurotransmission, including the FEF and caudate23;24. This proposal will examine the relationship between eye tracking and the density of the dopamine transporter (DAT) in the FEF and caudate in schizophrenia and healthy controls. A second focus will be on the effect of a functional variable number of tandem repeats (VNTR) polymorphism in the dopamine transporter gene (DAT1) and DAT density in the FEF and caudate. DAT density is measured by the binding potential of the DAT-specific radioligand, [11C]WIN 35,428, during Positron Emission Tomography (PET) scan. The study's approach integrates ex vivo molecular biochemistry, functional genomics, and in vivo neuroimaging methodologies. PUBLIC HEALTH RELEVANCE: A pilot study to examine the relationship between a heritable schizophrenia biomarker (eye tracking), DAT1 genotype, and the dopamine transporter density using PET radiotracer imaging.